Prior research strongly suggests that patients with affective disorders have abnormalities in the functioning of one or more neurobiological systems. At a conference convened by the Clinical Research Branch, NIMH, these findings were reviewed and some of the factors which were impeding movement towards a more complete and integrated view of the functioning of neurobiological systems in patients with mania or depression were identified. As a result, the NIMH sponsored the development of a multiresearch center, collaborative approach to the study of the psychobiology of affective disorders. In this collaborative program, underway for several years, the major objectives have been the testing of a wide range of hypotheses which implicate neurochemistry in the etiology and maintenance of the affective disorders. In order to accomplish this, the focus has been upon: (a) the assessment of the functioning of several different types of biological systems in the same patient both before and during treatment; (b) obtaining a large number of patients and comparison subjects; and (c) the use across centers of standardized diagnostic categories and behavioral methodologies. During the preceding grant period the data have been consolidated and data analysis has begun. Preliminary results have been reported and a range of studies are in progress. The specific aim of this proposal is the continuation of the testing of earlier, as well as current, hypotheses related to the behavioral and physiological pathology, as well as to treatment responsivity which may characterize depressed patients and differentiate them from healthy subjects.